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Targeted Gene Repair Therapy for Multisystemic Smooth Muscle Dysfunction Syndrome (MSMDS) Caused by ACTA2 R179H Mutation

Award Number: U01NS142895
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2029

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Targeted Gene Repair Therapy for Multisystemic Smooth Muscle Dysfunction Syndrome (MSMDS) Caused by ACTA2 R179H Mutation - Abstract Pathogenic missense variants in the ACTA2 gene at arginine 179 (most commonly replacement by histidine) cause a severe Ultra-Rare syndrome termed Multisystem smooth muscle dysfunction syndrome (MSMDS) characterized by systemic smooth muscle cell (SMC) dysfunction causing hypotension, aortic aneurysms and devastating cerebrovascular disease that leads to neurodegeneration and death in the first 3 decades of life. The recurrent nature of the mutation and the severity of the disorder make MSMDS a candidate for genomic editing approaches. In this proposal we present proof of concept data in animal models of a novel gene therapeutic approach to treat MSMDS involving a novel CRISPR/Cas9-directed Adenine Base Editor (ABE) to correct the most common mutation (ACTA2 c.536G>A, p.R179H). The ABE is delivered to the vasculature by a novel AAV vascular-targeting capsid named AAV-PR. We noted complete rescue of multiple clinical phenotypes in a mouse model of MSMDS accompanied by efficient levels of correction of the mutation. In this proposal we propose IND-enabling studies including: GLP and GMP drug product (DP) production, completion of POC studies, murine and NHP toxicity studies, as well as clinical and regulatory development activities. We provide a comprehensive plan to enable an IND application for a novel genomic editing gene therapeutic by the end of the proposal period.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $2,541,084 )
2026	2026	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	5/5/2026	NEW	$2,541,084
														Subtotal = $2,541,084

Grand Total All Awards = $2,541,084

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Targeted Gene Repair Therapy for Multisystemic Smooth Muscle Dysfunction Syndrome (MSMDS) Caused by ACTA2 R179H Mutation

Award Number: U01NS142895

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 05/01/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2029

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